Regulation of blood glucose is impaired in diabetes by the inability of the pancreas to adequately produce the glucose-regulating hormone insulin and by the insensitivity of various tissues that use insulin to take up glucose. To correct this disregulation requires blood glucose monitoring.
Currently, glucose monitoring in the diabetic population is based largely on collecting blood by “fingersticking” and determining its glucose concentration by conventional assay. This procedure has several disadvantages, including: (1) the discomfort associated with fingersticking, which should be performed repeatedly each day; (2) the near impossibility of sufficiently frequent sampling (some blood glucose excursions require sampling every 20 minutes, or less, to accurately treat); and (3) the requirement that the user initiate blood collection, which precludes warning strategies that rely on automatic early detection. Using the present procedure, the frequent sampling regimen that would be most medically beneficial cannot be realistically expected of even the most committed patients, and automatic sampling, which would be especially useful during periods of sleep, is not available.
Implantable glucose sensors have long been considered as an alternative to intermittent monitoring of blood glucose levels by the fingerstick method of sample collection. The operability of one such sensor has been demonstrated as a central venous implant in dogs (Armour, et al., Diabetes, 39:1519–1526 (1990). Although this sensor provided a continuous recording of blood glucose, which is most advantageous for clinical applications, implantation at a central venous site poses risks of blood clot formation and vascular wall damage. The alternative is to implant the sensor in a solid tissue site and to relate the resulting signal to blood glucose concentration.
Typical sensors implanted in solid tissue sites measure the concentration of polar solutes; such as glucose, in the blood perfusing the microcirculation in the vicinity of the sensor. Glucose diffuses from nearby capillaries to the sensor surface. Because such diffusion occurs effectively only over very small distances, the sensor responds to the substrate supply only from nearby blood vessels. Conversely, solutes that are generated in the locality of the sensor may be transported away from the sensor's immediate vicinity by the local microvasculature. In either case, the local microcirculation may influence the sensor's response.
One problem that has confronted previous attempts to implant sensors in solid tissue is that the pattern of blood vessels in the vicinity of the sensor may be highly variable, and may change with time in response to the implantation procedure and the presence of an implant. In some cases, microscopic blood vessels may be close to the sensing element, resulting in substantial diffusive flux and clear, strong signals. In other cases, blood vessels are more distant and sensors appear not to function, to function weakly, or to function only with substantial delays.
Further complicating the spatial inhomogeneity of the microvasculature are the phenomena of vasomotion and variations in regional blood flow. Vasomotion describes the unsynchronized stop-start blood flow cycles that are observed in individual capillaries in living tissue. This phenomenon is characterized by spatial asynchrony—some capillaries have flow while immediate neighbors do not. Vasomotion does not occur continuously or frequently and may be most common when the tissue is otherwise at rest. But, when it occurs, the frequency is about 2 to 4 cycles per minute, with flow interruption in individual capillaries ranging from partial to complete.
Regional blood flow is also affected by posture and the position of the body, such-that localized surface pressure on a blood vessel may occlude it completely, albeit temporarily. The occurrence of such complete occlusion is, of course, not predictable.
Although using biocompatible materials can minimize the tissue response to the implant, capillary distributions or diffusion resistances may still be affected, altering the diffusive flux to the sensor. As such, there is a compelling need for a sensor designed to accommodate the variability of the microvascular structure of solid tissue.